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Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation

Abstract

c-Jun is a major component of the heterodimeric transcription factor AP-1 and is essential for embryonic development, as fetuses lacking Jun die at mid-gestation1,2 with impaired hepatogenesis1 and primary Jun–/– fibroblasts have a severe proliferation defect and undergo premature senescence in vitro2. c-Jun and AP-1 activities are regulated by c-Jun N-terminal phosphorylation (JNP) at serines 63 and 73 through Jun N-terminal kinases3,4 (JNKs). JNP is thought to be required for the anti-apoptotic function of c-Jun during hepatogenesis, as mice lacking the JNK kinase SEK1 exhibit liver defects similar to those seen in Jun–/– fetuses5. To investigate the physiological relevance of JNP, we replaced endogenous Jun by a mutant Jun allele with serines 63 and 73 mutated to alanines (Juntm1Wag; hereafter referred to as JunAA). Here we show that primary JunAA fibroblasts have proliferation- and stress-induced apoptotic defects, accompanied by reduced AP-1 activity. JunAA mice are viable and fertile, smaller than controls and resistant to epileptic seizures and neuronal apoptosis induced by the excitatory amino acid kainate. Primary mutant neurons are also protected from apoptosis and exhibit unaltered JNK activity. Our results provide evidence that JNP is dispensable for mouse development, and identify c-Jun as the essential substrate of JNK signalling during kainate-induced neuronal apoptosis.

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Figure 1: Generation and characterization of JunAA mice.
Figure 2: Characterization of fibroblasts lacking JNP.
Figure 3: Decreased kainate-induced seizures and neuronal apoptosis in JunAA mice.
Figure 4: JunAA neurons are protected from kainate-induced apoptosis in vitro.

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Acknowledgements

We are grateful to H.-C. Theuβl for blastocyst injection; R. Kupinski for maintaining our mouse colony; R. Kurzbauer for DNA sequencing; J.-P. David, C. Giefers and K. Sabapathy for help and discussion; R. Johnson for the Jun genomic clone; P. Vassalli for the CAGGS-cre plasmid; A. Nordheim for the E74-luciferase plasmid; A. Aguzzi, P. Angel, M. Cotten and K. Nasmyth for critical reading of the manuscript; and H. Tkadletz for help with preparing the illustrations. Supported in part by a grant from the Austrian Science Foundation (S7406-MOB) and the Austrian Industrial Research Promotion Fund.

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Correspondence to Erwin F. Wagner.

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Behrens, A., Sibilia, M. & Wagner, E. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21, 326–329 (1999). https://doi.org/10.1038/6854

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